Photodiagnosis and Photodynamic Therapy (2005) 2, 273—281
REVIEW
Systemic photodynamic therapy with Photofrin for naevoid basal cell carcinoma syndrome—–A pilot study V. Madan a, J. Loncaster b, D. Allan c, J. Lear a, L. Sheridan b, C. Leach b, E. Allan FRCR b,∗ a
Dermatology Centre, Hope Hospital, Salford, Manchester, UK Department of Clinical Oncology, Christie Hospital (NHS) Trust, Manchester, UK c North Western Medical Physics, Christie Hospital (NHS) Trust, Manchester, UK b
Available online 18 November 2005 KEYWORDS Basal call carcinoma; Gorlin’s syndrome; Naevoid basal cell carcinoma syndrome; Photodynamic therapy; Photofrin; Porfimer sodium; Optical fibre diffuser laser
∗
Summary Background: Treatment of basal cell carcinomas in naevoid basal cell carcinoma syndrome (NBCCS) poses several challenges. The sheer numbers of such lesions in these patients makes traditional therapeutic modalities like surgery, impractical. Topical photodynamic therapy (PDT) with ␦-5-amino levulinic acid has increasingly been recognised as and safe and effective choice in the treatment of BCC. The probability of local control of BCC treated by PDT depends strongly on lesion thickness, thick nodular lesions being less responsive. Response to treatment is monitored by the reduction in the lesional size, but histopathological confirmation of regression is often required. Method: We used systemic photodynamic therapy with Porfimer Sodium (Photofrin® , Axcan Pharma Inc., Quebec, Canada), a systemic photosensitizer for treating multiple BCC in seven patients with NBCCS. Treatment response was monitored using a high resolution 20 MHz ultrasound. Results: There was a substantial reduction in the number of superficial basal cell carcinomas with complete US regression after one treatment. A 74.2% reduction was seen in the size of thick lesions treated with external light. Thick nodular lesions in two patients treated with interstitial optical diffuser fibres in addition to external light showed 87.6% reduction in size as measured by high resolution ultrasound. Conclusions: Our preliminary results indicate that systemic photodynamic therapy using Photofrin and external light either alone or with interstitial optical diffuser fibres; may be effective in treatment of multiple, thick and nodular BCC lesions in Naevoid basal cell carcinoma syndrome. Further studies are needed to confirm our observations. We found high resolution ultrasound an effective alternative to histopathological analysis in monitoring the response to treatment. © 2005 Elsevier B.V. All rights reserved.
Corresponding author. E-mail address: [email protected] (E. Allan).
1572-1000/$ — see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/S1572-1000(05)00101-8
274
V. Madan et al.
Contents Introduction ..................................................................................................... Materials and methods .......................................................................................... Photodynamic therapy........................................................................................... Pulsed ultrasound ............................................................................................... Results .......................................................................................................... Discussion ....................................................................................................... References ......................................................................................................
Introduction The naevoid basal cell carcinoma syndrome (NBCCS) (syn: Gorlin’s syndrome, Gorlin-Goltz syndrome, basal cell naevus syndrome) is an autosomal dominant disorder characterised by appearance of numerous BCCs at an early age associated with various skeletal abnormalities, odontogenic cysts, palmoplantar pits and intracranial calcification owing to a mutation in patched suppressor gene (PTCH) that negatively regulates the hedgehog signalling pathway [1—3]. Gorlin subjects are uncommon (prevalence of 1/56,000 in the North West of England) [4], but they represent a greatly disproportionate skin cancer management problem. The overwhelming numbers, extensive nature and rate of evolution of BCCs in patients with NBCCS make the management of these lesions very difficult. Until recently, surgical excision with or without complex wound closure techniques and cryotherapy were the mainstay in the management of diffuse basal cell cancers in individuals with NBCCS. Surgical excision, cryotherapy, intralesional interferon alpha-2b and carbon dioxide laser vaporisation have been used with variable success [5]. Cumulative surgery, cryotherapy and other conventional interventions result in significant disfigurement by middle age. Such surgical or ablative procedures cause scarring and disfigurement and may increase morbidity. Photodynamic therapy is a relatively new approach to the treatment of certain cancers and non-malignant conditions [6]. It involves the topical or systemic administration of a photosensitizer and subsequent local application of photoactivating light to the diseased tissue. The photochemical reactions thus induced lead to destruction of the treated lesion. Successful treatment of superficial and small nodular basal cell carcinomas in NBCCS with topical ALA-PDT has been demonstrated [7,8]. Topical PDT using ALA has been shown to be an effective and safe alternative to surgery in the treat-
274 275 275 275 275 277 280
ment of multiple BCCs in children with NBBCS [9]. In addition to tissue sparing benefits, this technique has the advantage of achieving good cosmesis [10]. However, the treatment of nodular BCC with ALA-PDT has been associated with high recurrence rates despite the apparently favourable early responses based on clinical assessment [10]. Moreover, treatment of large areas of BCC in NBCCS with topical PDT poses practical problems of keeping the photosensitizer cream in place, difficulty in achieving a homogenous distribution of the sensitizer and in achieving pain control during light therapy. On the other hand, systemic photodynamic therapy with Photofrin circumvents these problems and the procedure is painless. Ultrasound imaging of the skin is a useful noninvasive technique for pre- and post-therapeutic assessment of BCC. Resolution of BCC after ALA-PDT can be quantified and non responsive lesions can be identified early using high resolution ultrasound, thus avoiding routine post treatment biopsies [11]. This method distinguishes regions rich in fibrous proteins, such as keratin in the epidermis and collagen in the dermis, as a series of echoes whose number and amplitude vary with the amount and orientation of protein bundles [12]. In contrast, BCCs are relatively hypoechogenoic enabling the differentiation of BCC sites after PDT with fibrosis regions caused by conventional treatments [11]. In this paper we describe our experience of systemic photodynamic therapy with porfimer sodium in treating multiple BCCs in patients with NBCCS and discuss the role of high resolution US in monitoring the response to therapy. The preliminary results are encouraging and indicate that treatment of multiple and nodular BCCs in NBCCS with systemic photodynamic therapy using Photofrin and either external light alone or in combination with diffuser fibres leads to complete resolution of large areas of superficial BCCs and substantial reduction in the size of thick lesions, as measured on high resolution US.
Systemic photodynamic therapy
Materials and methods The patients in this study were secondary or tertiary referrals from clinical geneticists, dermatologists, plastic and Moh’s surgeons, all of who were aware of photodynamic therapy. All had received more than one treatment for their lesions including topical five fluorouracil cream, laser, cryotherapy, radiotherapy, surgical resection, and Moh’s micrographic surgery. All but one patient had previously been treated with ALA-PDT. The decision to treat with systemic PDT was based on lack of response to treatment with other modalities including multiple treatments with ALA-PDT, wide and multiple areas of involvement and BCCs at difficult anatomical sites for ALA application (e.g. groin). All patients gave informed consent for the systemic PDT treatment and US measurements, ethical approval (South Manchester Ethics Committee).
Photodynamic therapy The photosensitizer used was Porfimer Sodium (Photofrin® , Axcan Pharma Inc., Quebec, Canada), administered intravenously at 1 mg/kg followed 48 h later by illumination with 630 nm red light via filtered xenon-arc lamp at 200 J/cm2 (Omnilux phototherapeutics Limited, Manchester, UK). In two patients with thick BCCs, light was delivered via interstitially placed 400 m diameter optical fibre with 2.5 mm cylindrical diffuser tip (Diomed® laser 630 PDT, Cambridge, UK) in addition to the external light source. The fibre was placed interstitially using an intravenous canula and bupivacaine was used for local anaesthesia. Laser was operated to deliver an output of 0.5 W and light was administered giving 1000 s exposure to attain exposure of 200 J/cm of fibre. The irradiance on the surface of the canula which was used to place the fibre interstitially was 373 mW/cm2 . As this procedure
275 is painless, no pre-procedure analgesia was administered. Patients were advised to avoid unnecessary light exposure for 1 month following treatment and analgesics (Acetaminophen and codeine) were prescribed for post procedure pain. Patients were followed up 1 month post treatment and thereafter depending upon the clinical and ultrasound response.
Pulsed ultrasound The instruments used was a 20 MHz, sharp-focussed two-dimensional ‘B’ scanner with a measurement length of 12 mm (=224 side-by-side ‘A’ scans), depth of measurement of 10 mm and resolution of 60 m × 130 m (Dermascan C ver. 3; Cortex Technology, Hadsund, Denmark). Both the maximum lesion thickness and the thickness of the adjacent normal skin were measured. The normal skin US findings were used to validate the reproducibility of repeated US measurements. Photographs were taken prior to first treatment so that the same areas could be identified and measured on follow-up. Data were saved to computer, with which a program proprietary to the US instrument converted echo delay times to distances by assuming a single velocity of sound through skin or lesion of 1580 m s−1 . The parameter measured for normal skin adjacent to any lesion, was thickness of epidermis plus dermis, defined as the section ‘a—b’ in Fig. 1B. The maximum thickness of the BCC was measured from the hypoechogenic region underlying the entry echo (‘c—d’ in Fig. 1B).
Results Our observations suggest that systemic PDT with porfimer sodium may be effective in the management of otherwise difficult to treat BCCs in
Figure 1 (A) Basal cell carcinoma in a patient with Gorlin’s syndrome. (B) High resolution ultrasound characteristics of the same lesion.
276
Table 1 No
Age
NBCCS patients Sex
Site treated
Previous treatments
Previous topical PDT
Light source
Number of treatments
Side effects
Ultrasound response Pre (mm)
Post (mm)
%
1
67
F
Cheek, inframammary area, upper back
5-FU, Rx, M, SE
No
Ext
1
Nil
1.89
0.33
82
2
55
F
Scalp
SE, L, C
x8
Ext
2
Crusting
2.30
0.4
82
3
57
F
Upper back
5-FU, SE
x5
Ext
4
Nil
2.7
0.6
77
4
30
Nose
5-FU, C, M
x3
Ext
1
Oedema
1.73
0.87
50
5
64
M
Face (cheek, nose, canthus)
5-FU, C, M
x3
Ext
1
Inflammation
1.74
0.47
73
6
43
M
Shoulder, cheek, forehead, temple
M, C, 5-FU
x2
Ext + fibre
1
Oedema
2.9
0.4
86
7
50
M
Forehead, scalp
C
x3
Ext + fibre
1
Nil
4.6
0.53
88
Response to treatment with systemic photodynamic therapy with Photofrin monitored with high resolution ultrasound. 5-FU, 5-fluorouracil; Rx, radiotherapy; M, Moh’s surgery; S, surgical excision; C, cryotherapy; L, laser.
V. Madan et al.
Systemic photodynamic therapy
277
Figure 2 (A, C, E) Basal cell carcinomas in Gorlin’s syndrome. (B, D, F) Clinical response after one treatment with Photofrin based systemic photodynamic therapy.
NBCCS (Table 1). Seven patients (three males, four females) with NBCCS were treated with systemic PDT. All patients had previously been treated with one or more conventional treatments. All but one patient had received 2—8 topical ALA-PDT treatments. The treatment was well tolerated by all patients and was painless. Self-limiting oedema and inflammation were the most noticeable side effects in three patients. Post procedure pain responded to oral analgesics containing codeine and acetaminophen. Post treatment prolonged phototoxicity; a theoretical side effect of porfimer sodium treatment was not seen in the present patient group. Pre treatment lesional
Table 2 Response to treatment as measured on high resolution US Number
Systemic PDT and external light Mean pre (mm)
Mean post (mm)
Mean % reduction in thickness
5
2.072
0.534
74.2
Number
Systemic PDT and external light + interstitial optical diffuser fibres
2
Mean pre (mm)
Mean post (mm)
Mean % reduction in thickness
3.75
0.465
87.6
278
Figure 3 Light delivery using interstitial optical fibre.
and normal skin US measurements were recorded (Fig. 4C and D). Clinical (Fig. 2A—F) and US response to porfimer sodium PDT was evident in most patients after one treatment. After a single treatment, thick BCC sites in five patients that showed clinical evidence of marked regression (mean reduction, 76%), had values of US parameters insignificantly different from normal skin (Table 1). In addition, smaller and
V. Madan et al. superficial lesions showed complete clinical and US regression (data not shown). Clinically thick and nodular lesions in patients 2 and 3 required 4 and 2 treatments, respectively to show significant clinical response (mean reduction, 80% after last treatment). Overall, 74.2% reduction was seen in the size of the lesions treated with Photofrin and external light (Table 2). Thick lesions in patients 6 and 7 were treated in addition to external light source with interstitial optical diffuser fibres as light delivery source (Fig. 3). Good response was achieved with this technique (mean reduction: 87.6%, Fig. 4A—D, Table 2). We are currently evaluating predictability of response to treatment based on ultrasound characteristics. Post-treatment US measurements correspond with the clinical response; lesions requiring more than one treatment were found to have a smaller proportional reduction in lesional thickness after first treatment. Excellent cosmesis was achieved in all patients.
Discussion The role of PDT in the Dermatology is well established. Various precancerous and malignant
Figure 4 Nodular basal cell cancer in a patient with Gorlin’s syndrome treated with Photofrin based systemic photodynamic therapy and light delivery using interstitial optical fibre. (A) Clinical appearance pretreatment. (B) Clinical response to treatment. (C) Pretreatment ultrasound characteristics of lesion. (D) Response measured on high resolution ultrasound.
Systemic photodynamic therapy tumours, preferentially actinic keratoses as well as basal cell and squamous cell carcinomas, have shown partial or complete clinical response to photodynamic treatment [13,14]. Porfimer Sodium (Photofrin® , Axcan Pharma Inc, Quebec, Canada), was the first photosensitizer approved for clinical PDT. Porfimer sodium a purified mixture of oligomeric porphyrins, administered intravenously followed by illumination with 630 nm laser light and is approved for the palliation of obstructing oesophageal cancer and small cell lung cancer, treatment of microinvasive non small-cell lung cancer and high grade dysplasia in patients with Barrett’s oesophagus [15]. It has also been successfully used in the treatment of Mediterranean and HIV-related Kaposi’s sarcoma and Bowen’s disease [16]. Its use in treatment of sporadic BCCs has been demonstrated by Wilson et al. [17] who treated 151 BCCs with 1.0 mg/kg of body weight of porfimer sodium and different light doses (72—288 J/cm2 ), obtaining a cure rate of 88% at 1—3 months after PDT. The remaining partially responsive tumours healed completely after a second PDT. During a follow-up period of 29 months, 16% of these lesions recurred. Most of these tumours were sclerodermiform BCCs indicating poor responsiveness of this histological BCC type to PDT. Our results are in keeping with the response rates seen by Wilson et al. although monitoring recurrences in NBCCS is impractical given the number of lesions that would require surveillance. Keller et al. [18] have reported a 100% cure rate in six BCC lesions, based on a 4-year follow up. The overall response rates of BCCs to systemic PDT lie within the range of 50—100% [19,20]. We have been using topical ALA based PDT for treatment of BCCs in patients with NBCCS and have found a similar response rate to sporadic population. Systemic PDT using haematoporphyrin derivative (HPD) has also been shown to be effective in the management of BCCs in NBCCS with observed cure rates of 80% [21]. Rifkin et al. [22] similarly achieved a complete cure of all 13 BCCs in a male patient, without any evidence of recurrence at 6 months after intravenous Tin Etiopurpurin (SnET2 )-based PDT. The cutaneous accumulation of porphyrin-based photosensitizing drugs and their slow clearance from the skin leads to long lasting cutaneous photosensitivity, requiring photoprotective measures during 4—6 weeks after PDT [23,24]. ALA has been the most popular topical photosensitizer in the PDT of BCCs. Cure rates for superficial BCC’s range from 79 to 100% [25—27]. Nodular and noduloulcerative BCCs in contrast show a response rate of 10—50%, owing to the
279 limited penetration of ALA into the deeper layers of these tumours [25—30]. While 635-nm light may penetrate up to 6 mm, the therapeutically effective maximum depth of PDT will depend on sufficient light dose being delivered to tissue that also has sufficient photosensitizer to achieve a photodynamic reaction. The therapeutically effective depth of PDT in the skin is likely to be less, at 1—3 mm at 635 nm, depending on the tissue [33]. Rigid fibres coupled to the fibreoptics, which diffuse light circumferentially 360◦ perpendicular to their axis, may be placed interstitially and deliver light to the centre of bulky tumours [13]. This technique was successful in treating thick nodular BCCs in three of our patients. Therefore, the choice of photosensitizer would depend upon its pharmacokinetics and the ability to achieve sufficient concentration within the malignant lesion. Perhaps, the most important factor in choosing the route of administration of photosensitizer is the characteristic of the lesion to be targeted. While topical ALA-PDT offers the convenience of shorter application to treatment time and avoidance of risk of prolonged photosensitization, it is important to emphasize the potential of systemic PDT in patients with multiple, thick widely distributed lesions, including those in NBCCS. Systemic PDT may be advantageous for thick nodular BCC and recurrent BCC, where maximizing depth of light and photosensitizer penetration is of particular importance. The method is painless which is another advantage of systemic PDT. Post treatment pain is well tolerated and responds to opiate containing analgesics (codeine and acetaminophen). The cosmetic outcome of both topical and systemic PDT has been reported to be good although no formal method of assessment of this parameter exists. The adverse influence of greater BCC thickness on the clinical outcome of ALA-PDT has been established using invasive biopsy or surgical resection [34,35]. We used 20 MHz high resolution US for assessing the response to treatment. It has been shown that pulsed US provides scans or images of skin or tumour, that closely correlate with thickness as measured by biopsy, for a variety of clinical lesions including BCC [36]. As shown previously, this instrument replaces the need for repeated and multiple skin biopsies and provides a non-invasive means of monitoring the response of BCCs to ALAPDT [11], and as shown here, systemic PDT. Pulsed ultrasound measurements of initial lesion thickness may therefore perform a useful triage function and provide an indicator of the likely necessity for more than one or alternative treatments to achieve a cure, which in case of widespread and thick lesions in NBCCS may be systemic PDT.
280 Thus, while topical PDT is an efficacious treatment for solitary or multiple superficial BCCs, our preliminary results indicate that systemic PDT may be useful for thick, nodular and resistant BCCs in patients with NBCCS.
References [1] Gorlin RJ. Nevoid basal cell carcinoma (Gorlin) syndrome. Genet Med 2004;6(November—December (6)):530—9. [2] Bale AE, Yu KP. The hedgehog pathway and basal cell carcinomas. Hum Mol Genet 2001;10(April (7)):757—62. [3] Quinn AG, Epstein Jr E. Patched, hedgehog, and skin cancer. Methods Mol Biol 2003;222:85—95. [4] Evans DG, Farndon PA, Burnell LD, Gattameni HR, Birch JM. The incidence of Gorlin syndrome in 173 consecutive cases of medulloblastoma. Br J Cancer 1991;64:959— 61. [5] Kopera D, Cerroni L, Fink-Puches R, et al. Different treatment modalities for the management of a patient with the nevoid basal cell carcinoma syndrome. J Am Acad Dermatol 1996 May;34(May (5 Pt 2)):937—9. [6] Dougherty TJ, Gomer CJ, Henderson BW. Photodynamic therapy. J Natl Cancer Inst 1998;90(June (12)):889— 905. [7] Itkin A, Gilchrest BA. delta-Aminolevulinic acid and blue light photodynamic therapy for treatment of multiple basal cell carcinomas in two patients with nevoid basal cell carcinoma syndrome. Dermatol Surg 2004;30(July (7)): 1054—61. [8] Dijkstra AT, Majoie IM, van Dongen JW. Photodynamic therapy with violet light and topical 6-aminolaevulinic acid in the treatment of actinic keratosis. Bowen’s disease and basal cell carcinoma. J Eur Acad Dermatol Venereol 2001;15(November (6)):550—4. [9] Oseroff AR, Shieh S, Frawley NP. Treatment of diffuse basal cell carcinomas and basaloid follicular hamartomas in nevoid basal cell carcinoma syndrome by wide-area 5aminolevulinic acid photodynamic therapy. Arch Dermatol 2005;141(January (1)):60—7. [10] Wolf P, Rieger E, Kerl H. Topical photodynamic therapy with endogenous porphyrins after application of 5aminolevulinic acid. An alternative treatment modality for solar keratoses, superficial squamous cell carcinomas, and basal cell carcinomas? J Am Acad Dermatol 1993;28(January (1)):17—21; Wolf P, Rieger E, Kerl H. Topical photodynamic therapy with endogenous porphyrins after application of 5aminolevulinic acid. An alternative treatment modality for solar keratoses, superficial squamous cell carcinomas, and basal cell carcinomas? J Am Acad Dermatol 1993;29(July (1)):41. [11] Allan E, Pye DA, Levine EL, Moore JV. Non-invasive pulsed ultrasound quantification of the resolution of basal cell carcinomas after photodynamic therapy. Lasers Med Sci 2002;17(4):230—7. [12] Moran CM, Bush NL, Bamber JC. Ultrasonic propagation properties of excised human skin. Ultrasound Med Biol 1995;21(9):1177—90. [13] Lui H, Anderson RR. Photodynamic therapy in dermatology: recent developments. Dermatol Clin 1993;11(January (1)):1—13. [14] Bissonnette R, Lui H. Current status of photodynamic therapy in dermatology. Dermatol Clin 1997;15(July (3)):507—19.
V. Madan et al. [15] AxcanPharmaInc Website: http://www.axcan.com/ photofrin/productinfo.php?lang=1. Accessed on June 18, 2005. [16] Calzavara-Pinton PG, Szeimies RM, Ortel B. Photodynamic therapy with systemic administration of photosensitizers in dermatology. J Photochem Photobiol B 1996;36(November (2)):225—31. [17] Wilson BD, Mang TS, Stoll H, Jones C, Cooper M, Dougherty TJ. Photodynamic therapy for the treatment of basal cell carcinoma. Arch Dermatol 1992;28(December (12)):1597—601. [18] Keller GS, Razum NJ, Doiron DR. Photodynamic therapy for non melanoma skin cancer. Facial Plast Surg 1989;6(Spring (3)):180—4. [19] Reynolds T. Photodynamic therapy expands its horizons. Natl Cancer Inst 1997;89(January (2)):112—24. [20] Roberts DJ, Cairnduff F. Photodynamic therapy of primary skin cancer: a review. Br J Plast Surg 1995;48(September (6)):360—70. [21] Tse DT, Kersten RC, Anderson RL. Hematoporphyrin derivative photoradiation therapy in managing nevoid basal-cell carcinoma syndrome. A preliminary report. Arch Ophthalmol 1984;102(July (7)):990—4. [22] Rifkin R, Reed B, Hetzel F, Chen K. Photodynamic therapy using SnET2 for basal cell nevus syndrome: a case report. Clin Ther 1997;19(July—August (4)):639—41. [23] Ochsner M. Photodynamic therapy: the clinical perspective. Review on applications for control of diverse tumorous and non-tumorous diseases. Arzneimittelforschung 1997;47(November (11)):1185—94. [24] Gomer CJ. Preclinical examination of first and second generation photosensitizers used in photodynamic therapy. Photochem Photobiol 1991;54(December (6)):1093— 107. [25] Wolf P, Rieger E, Kerl H. Topical photodynamic therapy with endogenous porphyrins after application of 5aminolevulinic acid. An alternative treatment modality for solar keratoses, superficial squamous cell carcinomas, and basal cell carcinomas? J Am Acad Dermatol 1993;28(January (1)):17—21. [26] Fijan S, Honigsmann H, Ortel B. Photodynamic therapy of epithelial skin tumours using delta-aminolaevulinic acid and desferrioxamine. Br J Dermatol 1995;133(August (2)):282—8. [27] Peng Q, Warloe T, Berg K, et al. 5-Aminolevulinic acid-based photodynamic therapy. Clinical research and future challenges. Cancer 1997;79(June (12)):2282—308. [28] Calzavara-Pinton PG. Repetitive photodynamic therapy with topical delta-aminolaevulinic acid as an appropriate approach to the routine treatment of superficial non-melanoma skin tumours. J Photochem Photobiol B 1995;29(July (1)):53—7. [29] Martin A, Tope WD, Grevelink JM, et al. Lack of selectivity of protoporphyrin IX fluorescence for basal cell carcinoma after topical application of 5-aminolevulinic acid: implications for photodynamic treatment. Arch Dermatol Res 1995;287(7):665—74. [30] Peng Q, Warloe T, Moan J, et al. Distribution of 5aminolevulinic acid-induced porphyrins in noduloulcerative basal cell carcinoma. Photochem Photobiol 1995;62(November (5)):906—13. [33] Morton CA. Photodynamic therapy for nonmelanoma skin cancer—–and more? Arch Dermatol 2004;140(January (1)):116—20. [34] Morton CA, MacKie RM, Whitehurst C, Moore JV, McColl JH. Photodynamic therapy for basal cell carcinoma: effect of tumor thickness and duration of photosensitizer applica-
Systemic photodynamic therapy tion on response. Arch Dermatol 1998;134(February (2)): 248—9. [35] Varma S, Wilson H, Kurwa HA, et al. Bowen’s disease, solar keratoses and superficial basal cell carcinomas treated by photodynamic therapy using a large-field incoherent
281 light source. Br J Dermatol 2001;144(March (3)):567— 74. [36] Fornage BD, McGavran MH, Duvic M, Waldron CA. Imaging of the skin with 20-MHz US. Radiology 1993;189(October (1)):69—76.
REVIEW
Systemic photodynamic therapy with Photofrin for naevoid basal cell carcinoma syndrome—–A pilot study V. Madan a, J. Loncaster b, D. Allan c, J. Lear a, L. Sheridan b, C. Leach b, E. Allan FRCR b,∗ a
Dermatology Centre, Hope Hospital, Salford, Manchester, UK Department of Clinical Oncology, Christie Hospital (NHS) Trust, Manchester, UK c North Western Medical Physics, Christie Hospital (NHS) Trust, Manchester, UK b
Available online 18 November 2005 KEYWORDS Basal call carcinoma; Gorlin’s syndrome; Naevoid basal cell carcinoma syndrome; Photodynamic therapy; Photofrin; Porfimer sodium; Optical fibre diffuser laser
∗
Summary Background: Treatment of basal cell carcinomas in naevoid basal cell carcinoma syndrome (NBCCS) poses several challenges. The sheer numbers of such lesions in these patients makes traditional therapeutic modalities like surgery, impractical. Topical photodynamic therapy (PDT) with ␦-5-amino levulinic acid has increasingly been recognised as and safe and effective choice in the treatment of BCC. The probability of local control of BCC treated by PDT depends strongly on lesion thickness, thick nodular lesions being less responsive. Response to treatment is monitored by the reduction in the lesional size, but histopathological confirmation of regression is often required. Method: We used systemic photodynamic therapy with Porfimer Sodium (Photofrin® , Axcan Pharma Inc., Quebec, Canada), a systemic photosensitizer for treating multiple BCC in seven patients with NBCCS. Treatment response was monitored using a high resolution 20 MHz ultrasound. Results: There was a substantial reduction in the number of superficial basal cell carcinomas with complete US regression after one treatment. A 74.2% reduction was seen in the size of thick lesions treated with external light. Thick nodular lesions in two patients treated with interstitial optical diffuser fibres in addition to external light showed 87.6% reduction in size as measured by high resolution ultrasound. Conclusions: Our preliminary results indicate that systemic photodynamic therapy using Photofrin and external light either alone or with interstitial optical diffuser fibres; may be effective in treatment of multiple, thick and nodular BCC lesions in Naevoid basal cell carcinoma syndrome. Further studies are needed to confirm our observations. We found high resolution ultrasound an effective alternative to histopathological analysis in monitoring the response to treatment. © 2005 Elsevier B.V. All rights reserved.
Corresponding author. E-mail address: [email protected] (E. Allan).
1572-1000/$ — see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/S1572-1000(05)00101-8
274
V. Madan et al.
Contents Introduction ..................................................................................................... Materials and methods .......................................................................................... Photodynamic therapy........................................................................................... Pulsed ultrasound ............................................................................................... Results .......................................................................................................... Discussion ....................................................................................................... References ......................................................................................................
Introduction The naevoid basal cell carcinoma syndrome (NBCCS) (syn: Gorlin’s syndrome, Gorlin-Goltz syndrome, basal cell naevus syndrome) is an autosomal dominant disorder characterised by appearance of numerous BCCs at an early age associated with various skeletal abnormalities, odontogenic cysts, palmoplantar pits and intracranial calcification owing to a mutation in patched suppressor gene (PTCH) that negatively regulates the hedgehog signalling pathway [1—3]. Gorlin subjects are uncommon (prevalence of 1/56,000 in the North West of England) [4], but they represent a greatly disproportionate skin cancer management problem. The overwhelming numbers, extensive nature and rate of evolution of BCCs in patients with NBCCS make the management of these lesions very difficult. Until recently, surgical excision with or without complex wound closure techniques and cryotherapy were the mainstay in the management of diffuse basal cell cancers in individuals with NBCCS. Surgical excision, cryotherapy, intralesional interferon alpha-2b and carbon dioxide laser vaporisation have been used with variable success [5]. Cumulative surgery, cryotherapy and other conventional interventions result in significant disfigurement by middle age. Such surgical or ablative procedures cause scarring and disfigurement and may increase morbidity. Photodynamic therapy is a relatively new approach to the treatment of certain cancers and non-malignant conditions [6]. It involves the topical or systemic administration of a photosensitizer and subsequent local application of photoactivating light to the diseased tissue. The photochemical reactions thus induced lead to destruction of the treated lesion. Successful treatment of superficial and small nodular basal cell carcinomas in NBCCS with topical ALA-PDT has been demonstrated [7,8]. Topical PDT using ALA has been shown to be an effective and safe alternative to surgery in the treat-
274 275 275 275 275 277 280
ment of multiple BCCs in children with NBBCS [9]. In addition to tissue sparing benefits, this technique has the advantage of achieving good cosmesis [10]. However, the treatment of nodular BCC with ALA-PDT has been associated with high recurrence rates despite the apparently favourable early responses based on clinical assessment [10]. Moreover, treatment of large areas of BCC in NBCCS with topical PDT poses practical problems of keeping the photosensitizer cream in place, difficulty in achieving a homogenous distribution of the sensitizer and in achieving pain control during light therapy. On the other hand, systemic photodynamic therapy with Photofrin circumvents these problems and the procedure is painless. Ultrasound imaging of the skin is a useful noninvasive technique for pre- and post-therapeutic assessment of BCC. Resolution of BCC after ALA-PDT can be quantified and non responsive lesions can be identified early using high resolution ultrasound, thus avoiding routine post treatment biopsies [11]. This method distinguishes regions rich in fibrous proteins, such as keratin in the epidermis and collagen in the dermis, as a series of echoes whose number and amplitude vary with the amount and orientation of protein bundles [12]. In contrast, BCCs are relatively hypoechogenoic enabling the differentiation of BCC sites after PDT with fibrosis regions caused by conventional treatments [11]. In this paper we describe our experience of systemic photodynamic therapy with porfimer sodium in treating multiple BCCs in patients with NBCCS and discuss the role of high resolution US in monitoring the response to therapy. The preliminary results are encouraging and indicate that treatment of multiple and nodular BCCs in NBCCS with systemic photodynamic therapy using Photofrin and either external light alone or in combination with diffuser fibres leads to complete resolution of large areas of superficial BCCs and substantial reduction in the size of thick lesions, as measured on high resolution US.
Systemic photodynamic therapy
Materials and methods The patients in this study were secondary or tertiary referrals from clinical geneticists, dermatologists, plastic and Moh’s surgeons, all of who were aware of photodynamic therapy. All had received more than one treatment for their lesions including topical five fluorouracil cream, laser, cryotherapy, radiotherapy, surgical resection, and Moh’s micrographic surgery. All but one patient had previously been treated with ALA-PDT. The decision to treat with systemic PDT was based on lack of response to treatment with other modalities including multiple treatments with ALA-PDT, wide and multiple areas of involvement and BCCs at difficult anatomical sites for ALA application (e.g. groin). All patients gave informed consent for the systemic PDT treatment and US measurements, ethical approval (South Manchester Ethics Committee).
Photodynamic therapy The photosensitizer used was Porfimer Sodium (Photofrin® , Axcan Pharma Inc., Quebec, Canada), administered intravenously at 1 mg/kg followed 48 h later by illumination with 630 nm red light via filtered xenon-arc lamp at 200 J/cm2 (Omnilux phototherapeutics Limited, Manchester, UK). In two patients with thick BCCs, light was delivered via interstitially placed 400 m diameter optical fibre with 2.5 mm cylindrical diffuser tip (Diomed® laser 630 PDT, Cambridge, UK) in addition to the external light source. The fibre was placed interstitially using an intravenous canula and bupivacaine was used for local anaesthesia. Laser was operated to deliver an output of 0.5 W and light was administered giving 1000 s exposure to attain exposure of 200 J/cm of fibre. The irradiance on the surface of the canula which was used to place the fibre interstitially was 373 mW/cm2 . As this procedure
275 is painless, no pre-procedure analgesia was administered. Patients were advised to avoid unnecessary light exposure for 1 month following treatment and analgesics (Acetaminophen and codeine) were prescribed for post procedure pain. Patients were followed up 1 month post treatment and thereafter depending upon the clinical and ultrasound response.
Pulsed ultrasound The instruments used was a 20 MHz, sharp-focussed two-dimensional ‘B’ scanner with a measurement length of 12 mm (=224 side-by-side ‘A’ scans), depth of measurement of 10 mm and resolution of 60 m × 130 m (Dermascan C ver. 3; Cortex Technology, Hadsund, Denmark). Both the maximum lesion thickness and the thickness of the adjacent normal skin were measured. The normal skin US findings were used to validate the reproducibility of repeated US measurements. Photographs were taken prior to first treatment so that the same areas could be identified and measured on follow-up. Data were saved to computer, with which a program proprietary to the US instrument converted echo delay times to distances by assuming a single velocity of sound through skin or lesion of 1580 m s−1 . The parameter measured for normal skin adjacent to any lesion, was thickness of epidermis plus dermis, defined as the section ‘a—b’ in Fig. 1B. The maximum thickness of the BCC was measured from the hypoechogenic region underlying the entry echo (‘c—d’ in Fig. 1B).
Results Our observations suggest that systemic PDT with porfimer sodium may be effective in the management of otherwise difficult to treat BCCs in
Figure 1 (A) Basal cell carcinoma in a patient with Gorlin’s syndrome. (B) High resolution ultrasound characteristics of the same lesion.
276
Table 1 No
Age
NBCCS patients Sex
Site treated
Previous treatments
Previous topical PDT
Light source
Number of treatments
Side effects
Ultrasound response Pre (mm)
Post (mm)
%
1
67
F
Cheek, inframammary area, upper back
5-FU, Rx, M, SE
No
Ext
1
Nil
1.89
0.33
82
2
55
F
Scalp
SE, L, C
x8
Ext
2
Crusting
2.30
0.4
82
3
57
F
Upper back
5-FU, SE
x5
Ext
4
Nil
2.7
0.6
77
4
30
Nose
5-FU, C, M
x3
Ext
1
Oedema
1.73
0.87
50
5
64
M
Face (cheek, nose, canthus)
5-FU, C, M
x3
Ext
1
Inflammation
1.74
0.47
73
6
43
M
Shoulder, cheek, forehead, temple
M, C, 5-FU
x2
Ext + fibre
1
Oedema
2.9
0.4
86
7
50
M
Forehead, scalp
C
x3
Ext + fibre
1
Nil
4.6
0.53
88
Response to treatment with systemic photodynamic therapy with Photofrin monitored with high resolution ultrasound. 5-FU, 5-fluorouracil; Rx, radiotherapy; M, Moh’s surgery; S, surgical excision; C, cryotherapy; L, laser.
V. Madan et al.
Systemic photodynamic therapy
277
Figure 2 (A, C, E) Basal cell carcinomas in Gorlin’s syndrome. (B, D, F) Clinical response after one treatment with Photofrin based systemic photodynamic therapy.
NBCCS (Table 1). Seven patients (three males, four females) with NBCCS were treated with systemic PDT. All patients had previously been treated with one or more conventional treatments. All but one patient had received 2—8 topical ALA-PDT treatments. The treatment was well tolerated by all patients and was painless. Self-limiting oedema and inflammation were the most noticeable side effects in three patients. Post procedure pain responded to oral analgesics containing codeine and acetaminophen. Post treatment prolonged phototoxicity; a theoretical side effect of porfimer sodium treatment was not seen in the present patient group. Pre treatment lesional
Table 2 Response to treatment as measured on high resolution US Number
Systemic PDT and external light Mean pre (mm)
Mean post (mm)
Mean % reduction in thickness
5
2.072
0.534
74.2
Number
Systemic PDT and external light + interstitial optical diffuser fibres
2
Mean pre (mm)
Mean post (mm)
Mean % reduction in thickness
3.75
0.465
87.6
278
Figure 3 Light delivery using interstitial optical fibre.
and normal skin US measurements were recorded (Fig. 4C and D). Clinical (Fig. 2A—F) and US response to porfimer sodium PDT was evident in most patients after one treatment. After a single treatment, thick BCC sites in five patients that showed clinical evidence of marked regression (mean reduction, 76%), had values of US parameters insignificantly different from normal skin (Table 1). In addition, smaller and
V. Madan et al. superficial lesions showed complete clinical and US regression (data not shown). Clinically thick and nodular lesions in patients 2 and 3 required 4 and 2 treatments, respectively to show significant clinical response (mean reduction, 80% after last treatment). Overall, 74.2% reduction was seen in the size of the lesions treated with Photofrin and external light (Table 2). Thick lesions in patients 6 and 7 were treated in addition to external light source with interstitial optical diffuser fibres as light delivery source (Fig. 3). Good response was achieved with this technique (mean reduction: 87.6%, Fig. 4A—D, Table 2). We are currently evaluating predictability of response to treatment based on ultrasound characteristics. Post-treatment US measurements correspond with the clinical response; lesions requiring more than one treatment were found to have a smaller proportional reduction in lesional thickness after first treatment. Excellent cosmesis was achieved in all patients.
Discussion The role of PDT in the Dermatology is well established. Various precancerous and malignant
Figure 4 Nodular basal cell cancer in a patient with Gorlin’s syndrome treated with Photofrin based systemic photodynamic therapy and light delivery using interstitial optical fibre. (A) Clinical appearance pretreatment. (B) Clinical response to treatment. (C) Pretreatment ultrasound characteristics of lesion. (D) Response measured on high resolution ultrasound.
Systemic photodynamic therapy tumours, preferentially actinic keratoses as well as basal cell and squamous cell carcinomas, have shown partial or complete clinical response to photodynamic treatment [13,14]. Porfimer Sodium (Photofrin® , Axcan Pharma Inc, Quebec, Canada), was the first photosensitizer approved for clinical PDT. Porfimer sodium a purified mixture of oligomeric porphyrins, administered intravenously followed by illumination with 630 nm laser light and is approved for the palliation of obstructing oesophageal cancer and small cell lung cancer, treatment of microinvasive non small-cell lung cancer and high grade dysplasia in patients with Barrett’s oesophagus [15]. It has also been successfully used in the treatment of Mediterranean and HIV-related Kaposi’s sarcoma and Bowen’s disease [16]. Its use in treatment of sporadic BCCs has been demonstrated by Wilson et al. [17] who treated 151 BCCs with 1.0 mg/kg of body weight of porfimer sodium and different light doses (72—288 J/cm2 ), obtaining a cure rate of 88% at 1—3 months after PDT. The remaining partially responsive tumours healed completely after a second PDT. During a follow-up period of 29 months, 16% of these lesions recurred. Most of these tumours were sclerodermiform BCCs indicating poor responsiveness of this histological BCC type to PDT. Our results are in keeping with the response rates seen by Wilson et al. although monitoring recurrences in NBCCS is impractical given the number of lesions that would require surveillance. Keller et al. [18] have reported a 100% cure rate in six BCC lesions, based on a 4-year follow up. The overall response rates of BCCs to systemic PDT lie within the range of 50—100% [19,20]. We have been using topical ALA based PDT for treatment of BCCs in patients with NBCCS and have found a similar response rate to sporadic population. Systemic PDT using haematoporphyrin derivative (HPD) has also been shown to be effective in the management of BCCs in NBCCS with observed cure rates of 80% [21]. Rifkin et al. [22] similarly achieved a complete cure of all 13 BCCs in a male patient, without any evidence of recurrence at 6 months after intravenous Tin Etiopurpurin (SnET2 )-based PDT. The cutaneous accumulation of porphyrin-based photosensitizing drugs and their slow clearance from the skin leads to long lasting cutaneous photosensitivity, requiring photoprotective measures during 4—6 weeks after PDT [23,24]. ALA has been the most popular topical photosensitizer in the PDT of BCCs. Cure rates for superficial BCC’s range from 79 to 100% [25—27]. Nodular and noduloulcerative BCCs in contrast show a response rate of 10—50%, owing to the
279 limited penetration of ALA into the deeper layers of these tumours [25—30]. While 635-nm light may penetrate up to 6 mm, the therapeutically effective maximum depth of PDT will depend on sufficient light dose being delivered to tissue that also has sufficient photosensitizer to achieve a photodynamic reaction. The therapeutically effective depth of PDT in the skin is likely to be less, at 1—3 mm at 635 nm, depending on the tissue [33]. Rigid fibres coupled to the fibreoptics, which diffuse light circumferentially 360◦ perpendicular to their axis, may be placed interstitially and deliver light to the centre of bulky tumours [13]. This technique was successful in treating thick nodular BCCs in three of our patients. Therefore, the choice of photosensitizer would depend upon its pharmacokinetics and the ability to achieve sufficient concentration within the malignant lesion. Perhaps, the most important factor in choosing the route of administration of photosensitizer is the characteristic of the lesion to be targeted. While topical ALA-PDT offers the convenience of shorter application to treatment time and avoidance of risk of prolonged photosensitization, it is important to emphasize the potential of systemic PDT in patients with multiple, thick widely distributed lesions, including those in NBCCS. Systemic PDT may be advantageous for thick nodular BCC and recurrent BCC, where maximizing depth of light and photosensitizer penetration is of particular importance. The method is painless which is another advantage of systemic PDT. Post treatment pain is well tolerated and responds to opiate containing analgesics (codeine and acetaminophen). The cosmetic outcome of both topical and systemic PDT has been reported to be good although no formal method of assessment of this parameter exists. The adverse influence of greater BCC thickness on the clinical outcome of ALA-PDT has been established using invasive biopsy or surgical resection [34,35]. We used 20 MHz high resolution US for assessing the response to treatment. It has been shown that pulsed US provides scans or images of skin or tumour, that closely correlate with thickness as measured by biopsy, for a variety of clinical lesions including BCC [36]. As shown previously, this instrument replaces the need for repeated and multiple skin biopsies and provides a non-invasive means of monitoring the response of BCCs to ALAPDT [11], and as shown here, systemic PDT. Pulsed ultrasound measurements of initial lesion thickness may therefore perform a useful triage function and provide an indicator of the likely necessity for more than one or alternative treatments to achieve a cure, which in case of widespread and thick lesions in NBCCS may be systemic PDT.
280 Thus, while topical PDT is an efficacious treatment for solitary or multiple superficial BCCs, our preliminary results indicate that systemic PDT may be useful for thick, nodular and resistant BCCs in patients with NBCCS.
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